Psychotic diseases include anxiety, schizophrenia, dipolar disorder, etc. Schizophrenia is the most serious and harmful one among the psychotic diseases, and it is the seventh disease which contributes to the society burden. Its main clinical manifestation comprises thought disorder (thought broadcasting, thought withdrawal, thought poverty, delusion, etc.), hallucination, mood disorder (abepithymia, parathymia), behavior disorder (social withdrawal, bizarre behavior, catatonic excitement, stupor, etc.) and learning and working memory deficits. With the deterioration of social environment and the increasing life stress, the incidence of schizophrenia shows a clear upward trend.
In modern medicine, schizophrenia is considered as a syndrome, a collection of symptoms and signs with unclear causes. In the recent decade, the researches on neurotransmitters and receptors are active, and it is found that in some of the schizophrenic patients, the neuroendocrine is affected due to central neurotransmitter and receptor dysfunction. The above research result is used in clinic and for developing novel therapeutic drugs. Numerous researches show that psychotic diseases are associated with central monoamine neurotransmitter and receptor dysfunction, and the central dopamine (DA) system and 5-hydroxyl tryptamine (5-HT) system are closely related with the human psychomotility. Studies show that DA and 5-HT system dysfunction may lead to multiple neuropsychiatric diseases such as schizophrenia, depression, mania, anxiety, Parkinson's disease, neuropathic pain, etc.
At present, clinically available antipsychotic drugs mainly act on DA and 5-HT systems, which can be divided into classical antipsychotics and non-classical antipsychotics based on their mechanisms and targets. The former mainly acts on DA system (D2 receptor antagonist), while the latter mainly acts on DA system and 5-HT system (for example, D2/5-HT2a dual antagonist). The current first-line drugs in clinic are mainly non-classical antipsychotics. The classical antipsychotics may lead to side effects such as extrapyramidal system effect (EPS) and byperprolactinemia, etc. due to their superantagonism toward substantia nigra-striatum and tubero-infundibular D2 receptor. In addition, since they act on DA system alone, they are only effective for schizophrenic positive symptoms, and are ineffective for negative symptoms and cognitive impairment. Non-classical antipsychotics such as ziprasidone, risperidone, aripiprazole, quetiapine, etc. which can be used to treat positive symptoms also show some improvement effect on negative symptoms, although they cannot significantly improve cognitive impairment. All of them show corresponding side effects, such as higher EPS probability, obesity, akathisia, insomnia, anxiety, cardiotoxicity, etc. Therefore, there are no currently marketed drugs which can effectively reduce the above side effects while improving the whole spectrum of schizophrenia. Thus, the focus in developing antipsychotic drugs is to look for novel anti-schizophrenia drugs with high efficacy, low toxicity and wide treatment spectrum.
Five subtypes of dopamine receptors D1, D2, D3, D4 and Dg belong to two families, i.e. D1 family, which includes D1 and D5, and D2 family, which includes D2, D3 and D4. Currently, more researches are focused on D2 receptor family. D2 receptor in central system is mainly distributed in substantia nigra, corpus striatum, caudate nucleus, nucleus accumbens and limbic system. Existing antipsychotics exert their anti-schizophrenic positive symptom effect by antagonizing the D2 receptor. D3 receptor shows high homology to D2 receptor. Intracerebral D3 receptor is mainly distributed in mesencephalon cortex and limbic system. Blockage of D3 receptor will eliminate side effects such as extrapyramidal system (EPS) effect and the like, and is useful in treating catalepsy and improving cognition function in patients. Thus, a D3 receptor-selective antagonist has a favorable application prospect as an anti-schizophrenia drug. However, D3 receptor mRNA shows less distribution in the brain than D2 receptor. Thus, it is required that the drugs should possess D3 receptor selectivity when acting on D2 and D3 receptors both, that is to say, the drugs should possess 10 folds or higher affinity to D3 receptor than to D2 receptor so as to exert physiological effects on catalepsy, cognition improvement and the like. Numerous researches show that 5-HT2A receptor antagonists can remove the inhibition of dopaminergic neurons in limbic system to restore the normal function of dopaminergic neurons and thereby to improve the negative symptoms.
In recent years, the improvement effect of 5-HT1A receptor for reducing side effects of anti-schizophrenia drugs and improving cognition function has been gradually recognized in the academic community. It is demonstrated that the activation (or partial activation) of 5-HT1A can effectively reduce EPS and other side effects caused by excessive D2 blockage; in prefrontal cortex, NMDA (N-methyl-D-aspartic acid) receptor channel shares the same target as 5-HT1A receptor, and thus the action on 5-HT1A receptor in prefrontal cortex may facilitate the improvement of cognition function; and the activation of postsynaptic 5-HT1A receptor may reduce the release of glutamic acid, which helps to improve negative symptoms and cognition function. The partial activation of 5-HT1A and the synergism with D3 can reduce EPS below the observable level at therapeutic dosages. Therefore, novel anti-schizophrenia drugs which act on D2, D3, 5-HT1A and 5-HT2A receptor simultaneously and possess D3 selectivity have become a new direction in developing anti-schizophrenia drugs at present, and offer a guideline for the development of drugs for treating relevant diseases.
Cariprazine (RGH-188, with its chemical structure shown below) is a partial agonist of D2/D3/5-HT1A receptor jointly developed by Forest Laboratories and Gedeon Richter, which has passed Phase III clinical trial in USA, and now is at the registration stage. Its indications include schizophrenia, mania and depression. It is demonstrated by the results of receptor affinity tests that Cariprazine shows strong affinity to D2, D3 and 5-HT1A receptors (with the Ki values of 0.69 nM, 0.085 nM and 2.46 nM, respectively), moderate affinity to 5-HT2A receptor (with the Ki value of 19 nM), and a certain degree of D3/D2 receptor selectivity. In vivo tests demonstrates that it shows a clear efficacy with low toxicity and is unlikely to cause weight gain in patients of schizophrenia, depression and mania. It is further demonstrated by the clinical trials that Cariprazine shows good efficacy in treating manic depression. If it is successfully approved for the market, single drug treatment for manic depression will be realized for the first time, which will improve the compliance of the patients, and avoid the combination administration of anti-schizophrenia drugs and anti-depression drugs.
However, it is further demonstrated by the clinical trials that 22% of the patients who received Cariprazine at doses of 3 mg/d and 4.5 mg/d suffer from EPS, probably due to the excessively strong affinity to D2 receptor and the excessive blockage, or alternatively, due to that the effect on 5-HT1A receptor fails to completely improve the excessive blockage of D2 receptor. In animal experiments, Cariprazine shows good improvement effect on cognitive impairment, which, however, is not clearly demonstrated in clinical patients. This may be probably due to that the D3/D2 receptor selectivity is still insufficient to exhibit the improvement effect on D3 receptor-mediated cognition function.
